1. Field of the Invention
This invention relates to derivatives of 8-aryl-1,6-naphthyridin-5-ones useful as anti-inflammatory agents, immunosuppressive agents, anti-allograft rejection agents, anti-graft-vs-host disease agents, anti-allergic agents (e.g., asthma, rhinitis and atopic dermatitis), bronchodilation agents, anti-autoimmune agents or analgetic agents, to their precursors, to their preparation and to pharmaceutical compositions using the compounds of the invention.
2. Background Information
Cyclic 3', 5'-adenosine monophosphate (cAMP) modulates a variety of cellular and physiologic functions in mammals, such as, cell division, endocrine function, and the immune response. Several therapeutically beneficial effects arise from elevations in cAMP. For example, cAMP mediates airway smooth muscle relaxation, so a rise in the levels of cAMP should result in bronchodilation. Second, increased intracellular concentrations of cAMP in inflammatory cells prevents their activation thus reducing inflammation. Therefore, compounds which modulate cAMP are useful in treating diseases such as asthma where both bronchoconstriction and inflammation are implicated.
The level of cAMP is controlled by a class of enzymes called phosphodiesterases which enzymatically deactivate cAMP. There are five general types of phosphodiesterases which are categorized according to their function and the type of cell from which they are isolated. For instance, high-affinity phosphodiesterase (PDE III) is isolated from human platelet cells and modulates platelet aggregation. Another type of phosphodiesterase (PDE IV) is found in various tissues but is the predominant form in human leukocytes; this enzyme modulates leukocyte activation and function associated with the immune response and inflammation. PDE IV is the principal isozyme in almost all human inflammatory cells. Both of these phosphodiesterases implement their control by modulating the cellular level of cAMP in their respective cells. Thus, inhibition of phosphodiesterases provides a method of modulating any cellular and bodily function that is controlled by cAMP.
Compounds that are nonspecific phosphodiesterase inhibitors are known, i.e., these compounds inhibit all or multiple types of phosphodiesterases. [See, Beavo, J. A. and D. H. Reifsyder, Trends in Pharm. Science, 11:150-155 (1990); and Nicholson, C. D., R. A. J. Challiss and M. Shahid, Trends in Pharm. Science, 12:19-27 (1991).] Since cAMP is involved in so many functions throughout the body, a nonspecific phosphodiesterase inhibitor has the potential to alter all of the functions modulated by cAMP. Thus, nonspecific phosphodiesterase inhibitors are of limited value because of numerous side-effects.
By contrast, selective PDE inhibitors have demonstrable clinical utility. Selective PDE IV inhibitors show smooth muscle relaxant activity in human tracheal and bronchial preparations in vitro. Selective PDE IV inhibitors block mediator synthesis and release in mast cells, basophils, monocytes and eosinophils, reduce respiratory burst, chemotaxis and degranulation in neutrophils and eosinophils, and suppress mitogen-induced lymphocyte proliferation. Thus, a selective PDE IV inhibitor can provide both symptomatic (bronchodilation) and prophylactic (antiinflammatory) benefit in asthma. The mixed PDE III/IV inhibitor, zardarverine, exhibits bronchodilatory activity in asthmatic subjects and the selective PDE IV inhibitor, tibneblast prevents spontaneous bronchoconstriction in asthmatic subjects. In view of the anti-inflammatory effects of selective PDE IV inhibitors, such inhibitors find particular utility in the treatment of diseases such as asthma where both bronchoconstriction and inflammation occur.
It has been surprisingly discovered that certain derivatives of 8-phenyl-1,6-naphthyridin-5-ones are potent selective inhibitors of Phosphodiesterase Type IV (PDE IV) enzyme. These compounds are well suited for use as a treatment for any disorder in which PDE IV function plays a role, such as where leukocyte activation or function is involved. In particular, these compounds are especially well suited for use as anti-inflammatory agents, immunosuppressive agents, antiallograft rejection agents, anti-graft-vs-host disease agents, anti-allergic agents (e.g., asthma, rhinitis and atopic dermatitis), bronchodilation agents, anti-autoimmune disease agents or analgetic agents.